Krüppel-like Factors: Three Fingers in Many Pies

Abstract

Krüppel-like factor erythroid lung basic gut intestinal ubiquitous kidney fetal basic transcription element binding zinc finger core promoter-binding protein TGF-β-inducible early gene transforming growth factor cAMP-response element-binding protein (CREB)-binding protein AP2 repressor embryonic stem interferon familial adenomatous polyposis Krüppel-like factors (KLFs)1 are DNA-binding transcriptional regulators that play diverse roles during differentiation and development. They form a subset of the broad class of proteins containing Cys2/His2 zinc fingers, a motif that is the second most abundant seen in the human genome and the most abundant in transcription factors, estimated to be present in just under 600 to over 700 proteins (1Tupler R. Perini G. Green M.R. Nature. 2001; 409: 832-833Crossref PubMed Scopus (311) Google Scholar, 2Lander E.S. et al.Nature. 2001; 409: 860-921Crossref PubMed Scopus (18333) Google Scholar, 3Venter J.C. et al.Science. 2001; 291: 1304-1351Crossref PubMed Scopus (10873) Google Scholar). The nomenclature is based on the homology of its founding member, EKLF (erythroid Krüppel-like factor; KLF1), to theDrosophila Krüppel protein (4Miller I.J. Bieker J.J. Mol. Cell. Biol. 1993; 13: 2776-2786Crossref PubMed Scopus (667) Google Scholar). There are numerous finger proteins with such homology; however, the fact that KLF proteins contain additional conserved residues between each finger, that their fingers are three in number, and that these are found at the extreme carboxyl end serves to further define KLF proteins as a separate family (Fig. 1). Phylogenetic analysis of the 15 human KLF members demonstrates that they form a clade distinct even from the closely related Sp1 and Krox zinc finger families. Structural considerations also place these members together, as three amino acids at specific locations (“XYZ” positions (5Klevit R.E. Science. 1991; 253: 1367-1395Crossref PubMed Scopus (108) Google Scholar)) adjacent to the coordinating histidines play a determining role in target site selection and high affinity binding. As a result, all members of the family bind very similar “GT-box” or “CACCC element” sites on DNA, although the configuration is such that the site tends to be C-rich on one strand and G-rich on the other. The homologies and relationships among KLF family members, as well as their biological properties, have been the subject of excellent comprehensive reviews in the past 2 years (6Turner J. Crossley M. Trends Biochem. Sci. 1999; 24: 236-240Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 7Philipsen S. Suske G. Nucleic Acids Res. 1999; 27: 2991-3000Crossref PubMed Scopus (541) Google Scholar, 8Dang D.T. Pevsner J. Yang V.W. Int. J. Biochem. Cell Biol. 2000; 32: 1103-1121Crossref PubMed Scopus (380) Google Scholar). This discussion will focus on an update of the family and on recent experiments that demonstrate the wide and diverse range of cellular and molecular effects that are exerted by selected members (Fig.2). KLF6/ZF9/CPBP is rapidly induced in liver stellate cells that are activated after injury, leading to fibrogenesis and extracellular matrix formation (9Ratziu V. Lalazar A. Wong L. Dang Q. Collins C. Shaulian E. Jensen S. Friedman S.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9500-9505Crossref PubMed Scopus (238) Google Scholar). Consistent with this, KLF6 activates the collagen α1(I) promoter and the TGF-β promoters, establishing a link between KLF6 activity and cytokine responsiveness to injury (10Kim Y. Ratziu V. Choi S.G. Lalazar A. Theiss G. Dang Q. Kim S.J. Friedman S.L. J. Biol. Chem. 1998; 273: 33750-33758Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). This response is also seen in injured arterial endothelial cells, in which induced KLF6 expression up-regulates the urokinase plasminogen activator, leading to proteolytic activation of latent TGF-β and subsequent tissue remodeling (11Kojima S. Hayashi S. Shimokado K. Suzuki Y. Shimada J. Crippa M.P. Friedman S.L. Blood. 2000; 95: 1309-1316PubMed Google Scholar). Vascular injury also plays a role in the induction of KLF5/BTEB2/IKLF expression in smooth muscle cells, and phorbol ester-sensitive protein kinase pathways (particularly mitogen-activated protein kinase induction of Egr1 binding to the KLF5 promoter) have been implicated in directing this response (12Kawai-Kowase K. Kurabayashi M. Hoshino Y. Ohyama Y. Nagai R. Circ. Res. 1999; 85: 787-795Crossref PubMed Scopus (84) Google Scholar). In a similar (but not identical) way, KLF5 is a downstream target of Wnt1 signaling as judged by its induction after Wnt1 infection of cultured epithelia and after comparison of KLF5 levels in transgenic Wnt1 mouse mammary cells to wild type controls (13Ziemer L.T. Pennica D. Levine A.J. Mol. Cell. Biol. 2001; 21: 562-574Crossref PubMed Scopus (58) Google Scholar). Induction is transcriptional and occurs via a β-catenin/T cell factor-independent mechanism that may in